There is some evidence that the sulfonylurea hypoglycemic ("anti-diabetic") drugs cause increases in cardiac-related morbid events in maturity-onset diabetics. Recognizing the controversial nature of these findings the applicants point out that these drugs are known to have phototoxic effects. Spectroscopically, these drugs would be predicted to act as photosensitizers and preliminary results obtained by SDS-polyacrylamide gel electrophoresis indicate that they can cause a photoactivated molecular weight increase of serum albumin and can cause photoactivated changes in molecular weight of proteins of the sarcoplasmic reticulum from skeletal muscle. In the proposed research, several types of photodamage due to the antidiabetic drugs will be studied in five selected test systems: human serum albumin, serum lipoproteins, insulin, phospholipid vesicles and isolated sarcoplasmic reticulum. The types of damage to be assayed will include molecular fragmentation, irreversible molecular aggregation, amino acid residue oxidation, the appearance of oxidation products and loss of specific function. The quantum efficiency of photodamage due to irradiated antidiabetic drugs will be compared with that of well-studied photooxidizing agents (Rose Bengal, benzophenone). The correlations observed will be used to (a) evaluate the phototoxicity of these drugs in man and (b) will be used to establish quantitative criteria for evaluating possible phototoxic effects in new drugs. Photodamage will be investigated mechanistically to test for the involvement of free radical chain reactions.